The overall objectives of this Program Project Application are to test a relatively novel hypothesis of the etiology/pathogenesis of brain cell loss in aging and Alzheimer's Disease (AD). This hypothesis is: "Aging-related changes in mechanisms that regulate calcium homeostasis, both in serum and in the brain, increase susceptibility to neurotoxic influences, and are a primary etiologic factor in the acceleration of neurodegeneration that results in AD". Elevated intracellular calcium is well-established to be neurotoxic. If this hypothesis is found to be even partly correct, it will suggest new feasible and rational therapeutic approaches that could well have rapid impact on the treatment of AD and, therefore, could exert a major effect on human health and society. The Program Project (PP) consists of five projects and three cores which will test several subhypotheses of the initial causes of calcium dysregulation, including aging-related alterations in calcium regulating hormones (which have specific target sites in brain cells), in free-radical oxidation, in beta-amyloid accumulation, or in cerebral energy metabolism. There is indirect support for a role of each of these processes in neurotoxicity and glucocorticoid hormones have been found to facilitate brain cell loss in aging. The projects will test the effects of these putative causal factors on several models of aging and neuronal degeneration, including aged rats and brain cell cultures. In addition, however, correlational tests of these hypotheses will be conducted directly on autopsy brain tissues from AD subjects, as well as on calcium regulation in living AD subjects. These subjects and materials will be obtained from the UK Alzheimer's Disease Research Center at substantial cost savings. The PP investigators bring together a natural interest in the central theme, as well as multidisciplinary skills in advanced cellular techniques (ion channel recordings, molecular biology, biochemistry, imaging, etc.) and human studies (AD testing, calcium regulation, magnetic resonance imaging, etc.) and thus will provide a strongly integrated, multiple-level focus on the central hypothesis that would not be possible in a series of unrelated projects.